ALDH18A1-related De Barsy syndrome

ALDH18A1-related De Barsy syndrome is an extremely rare autosomal recessive disorder caused by biallelic pathogenic variants in the ALDH18A1 gene, which encodes the mitochondrial enzyme pyrroline-5-carboxylate synthase (P5CS). This enzyme plays a critical role in the biosynthesis of proline, ornithine, and citrulline. De Barsy syndrome is characterized by a distinctive combination of cutis laxa (loose, wrinkled, inelastic skin due to deficient elastic fibers), intellectual disability, and a progeroid (aged) facial appearance. The condition is sometimes referred to as De Barsy syndrome, progeroid type, or autosomal recessive cutis laxa type 3 (ARCL3). The disease affects multiple body systems. Dermatological features include generalized cutis laxa with thin, translucent skin that gives patients a prematurely aged appearance. Ophthalmological involvement is prominent and may include corneal clouding, cataracts, and other anterior segment abnormalities. Neurological manifestations include developmental delay, intellectual disability, hypotonia, and in some cases seizures. Growth retardation, joint hypermobility, and skeletal abnormalities such as osteopenia may also be present. Some patients exhibit adducted thumbs and movement disorders including athetosis or dystonia. There is currently no curative treatment for ALDH18A1-related De Barsy syndrome. Management is supportive and multidisciplinary, involving dermatologists, ophthalmologists, neurologists, and developmental specialists. Physical therapy and occupational therapy may help address motor delays and hypotonia. Surgical interventions may be considered for ophthalmological complications. Genetic counseling is recommended for affected families. The long-term prognosis varies depending on the severity of neurological and systemic involvement, and the condition can be associated with significant morbidity.

Common questions about ALDH18A1-related De Barsy syndrome